Doxycycline

Antibacterial

General indications

Doxycycline is a broad-spectrum antibiotic that is employed in the treatment of numerous bacterial infections. It is effective against bacteria such as Moraxella catarrhalis (a cause of respiratory tract infections), Brucella melitensis (a cause of brucellosis), Chlamydia pneumoniae (a cause of atypical pneumonia), and Mycoplasma pneumoniae (a cause of pneumonia). Additionally, doxycycline is used in the prevention and treatment of serious conditions like anthrax, leptospirosis, bubonic plague, and Lyme disease. However, some bacteria have developed resistance to doxycycline, including Haemophilus species, Mycoplasma hominis, and Pseudomonas aeruginosa.[18][19]

Specifically, doxycycline is indicated for treatment of the following diseases:[20][21]

• Rocky Mountain spotted fever, typhus fever and the typhus group, scrub typhus,[22] Q fever,[23] rickettsialpox, and tick fevers caused by Rickettsia,[24][25][26]
• respiratory tract infections caused by Mycoplasma pneumoniae,[27]
• Lymphogranuloma venereum, trachoma, inclusion conjunctivitis, and uncomplicated urethral, endocervical, or rectal infections in adults caused by Chlamydia trachomatis,[20][21]
• psittacosis,[20][21]
• non-gonococcal urethritis caused by Ureaplasma urealyticum,[20][21]
• relapsing fever due to Borrelia recurrentis,[20][21]
• chancroid caused by Haemophilus ducreyi,[20][21]
• plague due to Yersinia pestis,[20][21]
• tularemia,[20][21]
• cholera,[20][21]
• campylobacter fetus infections,[20][21]
• brucellosis caused by Brucella species (in conjunction with streptomycin),[20][21]
• bartonellosis,[20][21]
• granuloma inguinale (Klebsiella species),[20][21]
• Lyme disease (Borrelia species).
• Leptospirosis[28][29][30]

Indications for Gram-negative bacteria

When bacteriologic susceptibility testing (laboratory tests confirming the bacteria are sensitive to the drug) indicates appropriate susceptibility, doxycycline may be used to treat these infections caused by Gram-negative bacteria:[20][21]

• Escherichia coli infections,[20][21]
• Klebsiella aerogenes infections,[20][21]
• Shigella species infections,[20][21]
• Acinetobacter species infections,[20][21]
• respiratory tract infections caused by Haemophilus influenzae,[20][21]
• respiratory tract and urinary tract infections caused by Klebsiella species.[20][21]

Indications for Gram-positive bacteria

Some Gram-positive bacteria have developed resistance to doxycycline. Tetracycline resistance rates vary by geographic region; for example, resistance in Streptococcus pyogenes ranges from about 1% in Sweden to over 80% in China, and a pooled global resistance rate of approximately 67% has been reported for Enterococcus faecalis.[20][21] When bacteriologic susceptibility testing indicates appropriate susceptibility to the drug, doxycycline may be used to treat these infections caused by Gram-positive bacteria:[20][21]

• upper respiratory infections caused by Streptococcus pneumoniae,[20][21]
• skin and soft tissue infections caused by Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus (MRSA) infections,[20][21]
• anthrax caused by Bacillus anthracis infection.[20][21]

Penicillin contraindication

When penicillin is contraindicated, doxycycline can be used to treat:[20][21]

• syphilis caused by Treponema pallidum,[20][21]
• yaws caused by Treponema pertenue,[20][21]
• listeriosis due to Listeria monocytogenes,[20][21]
• Vincent's infection caused by Fusobacterium fusiforme,[20][21]
• actinomycosis caused by Actinomyces israelii,[20][21]
• infections caused by Clostridium species.[20][21]

Use as adjunctive therapy

Doxycycline is used as an adjunctive therapy for severe acne,[31][20][21] acute intestinal amebiasis,[32] and chancroid.[32]

Subantimicrobial-dose doxycycline (SDD) is widely used as an adjunctive treatment to scaling and root planing for periodontitis.[33] SDD is also used to treat skin conditions such as acne and rosacea,[14][34][35] including ocular rosacea. In ocular rosacea, treatment period is 2 to 3 months. After discontinuation of doxycycline, recurrences may occur within three months; therefore, many studies recommend either slow tapering or treatment with a lower dose over a longer period of time.[36]

As prophylaxis against sexually transmitted infections

Doxycycline is used as post-exposure prophylaxis (PEP) to prevent certain sexually transmitted infections, known as doxycycline post-exposure prophylaxis (doxyPEP). A landmark randomized trial in San Francisco found that a single 200 mg dose of doxycycline taken within 72 hours after condomless sex reduced the overall incidence of bacterial STIs by approximately two-thirds among men who have sex with men (MSM) and transgender women, with reductions of 87–88% for chlamydia, 73–87% for syphilis, and 55% for gonorrhea.[37] However, a separate trial found doxyPEP was not effective in cisgender women.[38]

In June 2024, the US Centers for Disease Control and Prevention (CDC) issued clinical guidelines recommending doxyPEP for MSM and transgender women with at least one bacterial STI in the prior 12 months.[39] The Australasian Society for HIV Medicine issued a more cautious consensus statement recommending doxyPEP only for syphilis prevention in MSM, citing concerns that the risk of increasing antimicrobial resistance, especially in Neisseria gonorrhoeae, outweighed the benefits for other STIs.[40] Use of doxyPEP has been associated with tetracycline resistance in N. gonorrhoeae.[41]

Use in combination

The first-line treatment for brucellosis is a combination of doxycycline and streptomycin. The second-line treatment is a combination of doxycycline and rifampicin (rifampin).[42]

Antimalarial

Doxycycline is active against the erythrocytic stages of Plasmodium falciparum, a protozoan parasite that causes malaria, but it is not active against the gametocytes of P. falciparum.[43] As such, doxycycline is used to prevent malaria,[44] but not recommended alone for initial treatment of malaria, even when the parasite is doxycycline-sensitive, because the antimalarial effect of doxycycline is delayed by 48 to 96 hours owing to a "delayed death" mechanism in which parasites complete their current replication cycle before dying in the next cycle. For this reason, doxycycline prophylaxis must be continued for four weeks after leaving a malarious area, compared with only seven days for atovaquone/proguanil.[45]

Doxycycline blocks protein production in the apicoplast (an organelle) of P. falciparum. This disrupts the parasite's ability to produce fatty acids, which are essential for its growth, and impairs the production of heme, a cofactor. These effects occur late in the parasite's life cycle during the blood stage (the erythrocytic cycle, when the parasite replicates inside human red blood cells).[46] By blocking important processes in the parasite, doxycycline both inhibits the growth and prevents the replication of P. falciparum. It does not directly kill living P. falciparum, but creates conditions that prevent their growth and replication.[47]

The World Health Organization (WHO) guidelines state that the combination of doxycycline with either artesunate or quinine may be used for the treatment of uncomplicated malaria due to P. falciparum or following intravenous treatment of severe malaria.[48]

Deworming

Doxycycline can be used against parasitic nematodes (worms) that cause filariasis. It kills symbiotic bacteria of the genus Wolbachia in the reproductive tracts of the nematodes, making the nematodes sterile (unable to reproduce).[49] This reduces transmission of diseases such as onchocerciasis and elephantiasis.[50] A randomized controlled trial showed that an eight-week course of doxycycline almost eliminates the release of microfilariae (larval offspring of the nematodes).[51]

Spectrum of susceptibility

Doxycycline has been used successfully to treat sexually transmitted, respiratory, and eye infections. Representative pathogenic genera include Chlamydia, Streptococcus, Ureaplasma, Mycoplasma, and others. The minimum inhibitory concentration for a few medically significant microorganisms are:[52]

• Chlamydia psittaci: 0.03 μg/mL[52]
• Mycoplasma pneumoniae: 0.016–2 μg/mL[52]
• Streptococcus pneumoniae: 0.06–32 μg/mL[52]

Sclerotherapy

Doxycycline is also used for sclerotherapy in venous and lymphatic malformations, as well as post-operative lymphoceles (collections of lymph fluid outside of lymphatic vessels).[53]

Off-label use

Doxycycline is used off-label in the treatment of transthyretin amyloidosis (ATTR). In combination with tauroursodeoxycholic acid, doxycycline has been shown to disrupt transthyretin (TTR) fibrils in existing amyloid deposits of ATTR patients, and is being investigated as a potential treatment option for this condition.[54]

Routes of administration

Doxycycline can be administered orally or intravenously.[3]

The combination of doxycycline with dairy, antacids, calcium supplements, iron products, laxatives containing magnesium, or bile acid sequestrants may decrease absorption of doxycycline, though these interactions are not inherently dangerous.[55]

Doxycycline has a high oral bioavailability, as it is almost completely absorbed in the stomach and proximal small intestine.[14] Unlike older tetracyclines, whose absorption is substantially reduced by food, doxycycline absorption is only modestly affected: co-administration of dairy products reduces the serum concentration of doxycycline by about 20%, compared with a 50% reduction for tetracycline.[14] Doxycycline absorption is inhibited by cations with a 2+ or 3+ charge (divalent and trivalent cations), such as iron, bismuth, aluminum, calcium, and magnesium.[14] Doxycycline forms unstable complexes with these metal ions in the acidic environment of the stomach; most of these complexes dissociate in the small intestine, allowing the drug to be absorbed. However, some doxycycline remains complexed with metal ions in the duodenum, resulting in a slight decrease in absorption.[14]

Pregnancy and lactation

Doxycycline is categorized by the FDA as a class D drug in pregnancy, meaning there is evidence of risk to the fetus but the benefits may outweigh the risks in certain situations. Doxycycline crosses into breast milk and is therefore a concern during breastfeeding.[57] Other tetracycline antibiotics are contraindicated in pregnancy and up to eight years of age, due to the potential for disrupting bone and tooth development.[58] The FDA includes a class warning for all tetracyclines about staining of teeth (typically yellow to brown discoloration) and decreased development of dental enamel in children exposed to tetracyclines in utero, during breastfeeding, or during early childhood (under eight years of age).[59] However, the FDA has acknowledged that the actual risk of dental staining of primary teeth is undetermined for doxycycline specifically. The best available evidence indicates that doxycycline has little or no effect on hypoplasia (underdevelopment) of dental enamel or on staining of primary teeth (baby teeth). The US Centers for Disease Control and Prevention (CDC) recommends the use of doxycycline for treatment of Q fever and tick-borne rickettsial diseases in children of all ages, and some researchers advocate for its use in children with malaria as well.[60]

Pharmacodynamics

Doxycycline, like other tetracycline antibiotics, is bacteriostatic. It works by preventing bacteria from reproducing by inhibiting protein synthesis.[71]

Doxycycline is highly lipophilic, so it can easily enter cells, meaning the drug is readily absorbed and has a large volume of distribution (it distributes widely throughout body tissues rather than remaining in the blood). It can also be re-absorbed in the renal tubules and gastrointestinal tract due to its high lipophilicity, giving it a long elimination half-life. In patients with kidney failure, doxycycline does not accumulate to toxic levels because the body compensates by increasing excretion through the feces.[62][72] Doxycycline-metal ion complexes are unstable in acidic conditions, therefore more doxycycline enters the duodenum for absorption than older tetracycline compounds such as tetracycline and oxytetracycline. In addition, food has less effect on the absorption of doxycycline than on other tetracyclines, with doxycycline serum concentrations being reduced by about 20% by test meals compared with 50% for tetracycline.[73]

Mechanism of action

Doxycycline is a broad-spectrum bacteriostatic antibiotic. It inhibits the synthesis of bacterial proteins by binding to the 30S ribosomal subunit, which is only found in bacteria.[61][72] This prevents the binding of transfer RNA to messenger RNA at the ribosomal subunit, meaning amino acids cannot be added to polypeptide chains and new proteins cannot be made. This stops bacterial growth, giving the immune system time to kill the bacteria.[74]

In rosacea treatment, doxycycline inhibits neutrophil chemotaxis and oxidative bursts (common mechanisms of inflammation and reactive oxygen species activity in rosacea), and it also suppresses matrix metalloproteases and kallikrein 5 which in turn reduce the expression of the human cathelicidin antimicrobial peptide (LL-37) and limit downstream inflammatory cascades.[75]

Absorption and excretion

Doxycycline is almost completely absorbed from the stomach and upper part of the small intestine (duodenum and jejunum). It reaches highest concentrations in the blood plasma after one to two hours and has a high plasma protein binding rate of about 80–90%. Doxycycline penetrates into almost all tissues and body fluids. Very high concentrations are found in the gallbladder, liver, kidneys, lungs, breast milk, bones, and genitals; low concentrations are found in saliva, aqueous humor, cerebrospinal fluid (CSF), and especially in inflamed meninges.[56][76][77] By comparison, the tetracycline antibiotic minocycline penetrates significantly better into the CSF and meninges.[78]

Doxycycline metabolism (breakdown by the body) is negligible. It is actively excreted into the gut (in part via the gallbladder, in part directly from blood vessels), where some of it is inactivated by forming chelates. About 40% are eliminated via the kidneys, much less in people with end-stage kidney disease. The biological half-life is 18 to 22 hours (16 ± 6 hours according to another source[76]) in healthy people, slightly longer in those with end-stage kidney disease, and significantly longer in those with liver disease.[56][76][77]

Chemical properties

Doxycycline, doxycycline monohydrate and doxycycline hyclate are yellow, crystalline powders with a bitter taste. The latter smells faintly of ethanol, a 1% aqueous solution has a pH of 2–3, and the specific rotation is −110° cm3/dm·g in 0.01 N methanolic hydrochloric acid.[76]

Brand names

Doxycycline is available worldwide under many brand names.[77]

Generic availability

Doxycycline is available as a generic medicine.[3][9]

Research reagent

Doxycycline and other members of the tetracycline class of antibiotics are often used as research reagents in in vitro and in vivo biomedical research experiments involving bacteria as well in experiments in eukaryotic cells and organisms with inducible protein expression systems using tetracycline-controlled transcriptional activation. The mechanism of action for the antibacterial effect of tetracyclines relies on disrupting protein translation in bacteria, thereby damaging the ability of microbes to grow and repair; however protein translation is also disrupted in eukaryotic mitochondria impairing metabolism and leading to effects that can confound experimental results.[96][97] Doxycycline is also used in "tet-on" (gene expression activated by doxycycline) and "tet-off" (gene expression inactivated by doxycycline) tetracycline-controlled transcriptional activation to regulate transgene expression in organisms and cell cultures.[98] Doxycycline is more stable than tetracycline for this purpose.[98] At subantimicrobial doses, doxycycline is an inhibitor of matrix metalloproteases,[75] and has been used in various experimental systems for this purpose, such as for recalcitrant recurrent corneal erosions.[99]

Medical conditions

Research areas on the application of doxycycline include the following medical conditions:

• macular degeneration;[100]
• rheumatoid arthritis instead of minocycline (both of which have demonstrated modest efficacy for this disease).[101]

Dosing

Although doxycycline is approved to treat Lyme disease, the optimal dosing and duration of treatment for this condition is a topic of ongoing research.[102] it can be used in adults and children. For treatment or prophylaxis of Lyme disease in children, it can be used for a duration of up to 21 days in children of any age.[103] Doxycycline is specifically indicated to treat Lyme disease for patients presenting with erythema migrans. As for the optimal duration of treatment of this disease, guidelines vary, with some recommending a 10-day course of doxycycline, while others suggest a 14-day course; still, recent data suggest that even a 7-day course of doxycycline can be effective. Compared to other drugs, there are no significant differences in treatment response across antibiotic agents, doses, or durations when comparing 14 days versus 21 days; as such, the optimal duration of treatment of Lyme disease remains uncertain, as prolonged antibiotic courses have drawbacks, including diminishing returns in terms of patient outcomes, heightened risks of adverse events, superinfections, increased healthcare costs, and the potential for development of antibiotic resistance. Therefore, the consensus remains to treat patients with the shortest effective duration of antibiotics, as is the case with doxycycline for Lyme disease as well.[104]

Anti-inflammatory agent

Some studies show doxycycline as a potential agent to possess anti-inflammatory properties acting by inhibiting proinflammatory cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and matrix metalloproteinases (MMPs)[75] while increasing the production of anti-inflammatory cytokines such as interleukin-10 (IL-10). Cytokines are small proteins that are secreted by immune cells and play a key role in the immune response. Some studies suggest that doxycycline can suppress the activation of the nuclear factor-kappa B (NF-κB) pathway, which is responsible for upregulating several inflammatory mediators in various cells, including neurons; therefore, it is studied as a potential agent for treating neuroinflammation.[105][106][107]

A potential explanation of doxycycline's anti-inflammatory properties is its inhibition of matrix metalloproteinases (MMPs),[75] which are a group of proteases known to regulate the turnover of extracellular matrix (ECM) and thus are suggested to be important in the process of several diseases associated with tissue remodeling and inflammation.[108][109][110][111] Doxycycline has been shown to inhibit MMPs,[75] including matrilysin (MMP7), by interacting with the structural zinc atom and/or calcium atoms within the structural metal center of the protein.[112][113][114]

Doxycycline also inhibits allikrein-related peptidase 5 (KLK5).[111] The inhibition of MMPs and KLK5 enzymes subsequently suppresses the expression of LL-37, a cathelicidin antimicrobial peptide that, when overexpressed, can trigger inflammatory cascades. By inhibiting LL-37 expression, doxycycline helps to mitigate these downstream inflammatory cascades, thereby reducing inflammation and the symptoms of inflammatory conditions.[111]

Doxycycline is used to treat acne vulgaris and rosacea.[115][116][14] However, there is no clear understanding of what contributes more: the bacteriostatic properties of doxycycline, which affect bacteria (such as Propionibacterium acnes[14]) on the surface of sebaceous glands even in lower doses called "submicrobial"[117][118] or "subantimicrobial",[119][120][121][14] or whether doxycycline's anti-inflammatory effects, which reduce inflammation in acne vulgaris and rosacea, including ocular rosacea,[36] contribute more to its therapeutic effectiveness against these skin conditions.[122] Subantimicrobial-dose doxycycline (SDD) can still have a bacteriostatic effect, especially when taken for extended periods, such as several months in treating acne and rosacea.[123] While the SDD is believed to have anti-inflammatory effects rather than solely antibacterial effects, SDD was proven to work by reducing inflammation associated with acne and rosacea. Still, the exact mechanisms have yet to be fully discovered.[124] One probable mechanism is doxycycline's ability to decrease the amount of reactive oxygen species (ROS). Inflammation in rosacea may be associated with increased production of ROS by inflammatory cells; these ROS contribute toward exacerbating symptoms. Doxycycline may reduce ROS levels and induce antioxidant activity because it directly scavenges hydroxyl radicals and singlet oxygen, helping minimize tissue damage caused by highly oxidative and inflammatory conditions.[125] Studies have shown that SDD can effectively improve acne and rosacea symptoms,[126] probably without inducing antibiotic resistance.[127] It is observed that doxycycline exerts its anti-inflammatory effects by inhibiting neutrophil chemotaxis and oxidative bursts, which are common mechanisms involved in inflammation and ROS activity in rosacea and acne.[75]

Doxycycline's dual benefits as an antibacterial and anti-inflammatory make it a helpful treatment option for diseases involving inflammation not only of the skin, such as rosacea and acne, but also in conditions such as osteoarthritis or periodontitis.[128] Nevertheless, current results are inconclusive, and evidence of doxycycline's anti-inflammatory properties needs to be improved, considering conflicting reports from animal models so far.[129][130][131] Doxycycline has been studied in various immunological disorders, including rheumatoid arthritis, lupus, and periodontitis.[132] In these conditions, doxycycline has been researched to determine anti-inflammatory and immunomodulatory effects that could be beneficial in treating these conditions. However, a solid conclusion still needs to be provided.[133][134][135][136]

Doxycycline is also studied for its neuroprotective properties which are associated with antioxidant, anti-apoptotic, and anti-inflammatory mechanisms. In this context, it is important to note that doxycycline is able to cross the blood–brain barrier. Several studies have shown that doxycycline inhibits dopaminergic neurodegeneration through the upregulation of axonal and synaptic proteins.[137][138] Axonal degeneration and synaptic loss are key events at the early stages of neurodegeneration and precede neuronal death in neurodegenerative diseases, including Parkinson's disease (PD). Therefore, the regeneration of the axonal and synaptic network might be beneficial in PD.[139] It has been demonstrated that doxycycline mimics nerve growth factor (NGF) signaling in PC12 cells. However, the involvement of this mechanism in the neuroprotective effect of doxycycline is unknown. Doxycycline is also studied in reverting inflammatory changes related to depression.[120] While there is some research on the use of doxycycline for treating major depressive disorder, the results are mixed.[120][140][141]

After a large-scale trial showed no benefit of using doxycycline in treating COVID19, the UK's National Institute for Health and Care Excellence (NICE) updated its guidance to not recommend the medication for the treatment of COVID19.[142][143] Doxycycline was expected to possess anti-inflammatory properties that could lessen the cytokine storm associated with a SARS-CoV-2 infection, but the trials did not demonstrate the expected benefit.[144] Researchers also believed that doxycycline possesses anti-inflammatory and immunomodulatory effects that could reduce the production of cytokines in COVID-19, but these supposed effects failed to improve the outcome of COVID-19 treatment.[145][146]

Wound healing

Research on novel drug formulations for the delivery of doxycycline in wound treatment is expanding, focusing on overcoming stability limitations for long-term storage and developing consumer-friendly, parenteral antibiotic delivery systems. The most common and practical form of doxycycline delivery is through wound dressings, which have evolved from mono- to three-layered systems to maximize healing effectiveness.[147]

Research directions on the use of doxycycline in wound healing include the continuous stabilization of doxycycline, scaling up technology and industrial production, and exploring non-contact wound treatment methods like sprays and aerosols for use in emergencies and when medical care is not readily accessible.[147]